Cocaine produces enduring alterations in nucleus accumbens core (NAcore) synaptic plasticity associated with relapse vulnerability. Specifically, cocaine self-administration causes enduring increases in dendritic spine head diameter, AMPA/NMDA ratios, and matrix metalloproteinase (MMP) activity. Re-exposure to cocaine- conditioned cues after extinction produces further rapid, transient synaptic potentiation (t-SP) within 15 min that is quantified with any of these measurements. However, when inducing reinstatement with a noncontingent cocaine injection the time course of t-SP differs in that the maximal response is not observed until 45 min. This discrepancy led to the hypothesis that while cues immediately drive forward drug seeking and t-SP, when reinstatement is initiated by noncontingent cocaine, the drug initially suppresses drug seeking and t-SP until pharmacological effects diminish below a threshold. A reinstatement model to evaluate this interaction between cue-induced cocaine seeking leading to cocaine use modeling many important features of human relapse was developed. Preliminary data show that contingent cocaine reverses cue-induced t-SP and discontinuation of this access rapidly restores t-SP. Cocaine increases synaptic dopamine (DA) as a competitive inhibitor of the dopamine transporter, thus dopaminergic mechanisms were hypothesized to contribute to cocaine's effects on cue-induced t-SP. Here, the role of cocaine-induced ventral tegmental area (VTA) DA transmission in t-SP reversal is examined using viral-based designer receptors exclusively activated by designer drugs (DREADD) and tyrosine hydroxylase-Cre (TH-Cre) transgenic rats to introduce anatomical and cell-type specificity. To accomplish this, the candidate will learn in vivo zymography to analyze MMP activity and patch clamp electrophysiology (Aim 1), as well as employ dendritic spine analysis and intracranial microinjection skills acquired during F32 NRSA training. In the K99 aims, the contribution of VTA DA in cocaine-induced reversal of NAcore t-SP will be characterized. Preliminary data show that cocaine-trained rats with Gq-DREADD in VTA TH+ cells will reinstate to a CNO priming injection and it will be further assessed whether this activation likewise blunts cue-induced t-SP. The impact of selective activation (Aim 2B) or inactivation of VTA DA cell bodies (Aim 2A) or terminal field regions (Aim 2C) on cue-induced t-SP and cocaine-induced suppression of t- SP will be examined. During the R00 period, chronic Gq-DREADD activation with CNO self-administration will be used to test the sufficiency for VTA DA activity to reproduce potentiated neuroplasticity produced by chronic cocaine (Aim 3). Furthermore, the dynamic regulation of glutamate and DA release in the reinstatement model will be assessed with microdialysis (Aim 4). These experiments have the potential to contribute to the development of novel therapeutic options aimed at reversing cocaine-induced neurobiological alterations.